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Two medicated mouthwashes led to reductions in oral mucositis pain for head and neck cancer patients treated with radiotherapy, but not at a level deemed clinically important, a randomized phase III study found.

Within 4 hours of radiotherapy, pain from oral mucositis dropped by 11.7 points (as defined by the area under the curve) with a diphenhydramine-lidocaine-antacid rinse -- or "magic mouthwash" -- and 11.6 points with a doxepin mouthwash, compared with 8.7 points with placebo, reported Robert C. Miller, MD, MS, MBA, of the University of Maryland School of Medicine in Baltimore, and colleagues.

Over 80% of radiotherapy- and chemoradiotherapy-treated head and neck cancer patients develop the painful and debilitating complication, with severe symptoms requiring hospitalization and feeding tubes, they explained. Systemic analgesics and mouthwashes are frequently used to manage the condition.

"For the diphenhydramine-lidocaine-antacid mouthwash, the current study provided the first evidence that the mouthwash appeared to be effective for short-term oral mucositis–related pain resulting from radiotherapy," Miller's group wrote in . "However, the mean differences in pain reduction by the area under the curve for both treatment intervention mouthwashes were less than the minimal clinically important difference of 3.5 points."

Compared with placebo, diphenhydramine-lidocaine-antacid led to a 3.0-point improvement (95% CI 0.1-5.9, P=0.004) while the doxepin mouthwash led to a 2.9-point improvement (95% CI 0.2-6.0, P=0.02).

"These data tell us that magic mouthwash (or doxepin) is not the sole answer to managing mucositis -- physicians should not prescribe magic mouthwash and expect magic!" Arjun Gupta, MD, of the Sidney Kimmel Comprehensive Cancer Center in Baltimore, told 番茄社区app in an email. "We have very few drugs to treat [these] patients in great suffering, and we need more drugs in well-designed trials to urgently address this question."

Gupta, who was not involved in the research, previously co-authored a calling into question the routine use of magic mouthwash for oral mucositis, with issues ranging from the limited efficacy, potential for high out-of-pocket costs, among other concerns.

"In the real world, there is no fixed formula for magic mouthwash. Most providers do not know the contents or concentrations of the ingredients in these mixed-medication formulations," he said. "They could also contain unnecessary and harmful ingredients such as steroids and antibacterials/antifungals. How many other drugs do physicians prescribe without knowing the contents or concentration?"

"Steroids, especially in a patient with dry mouth, may induce local secondary fungal infections that exacerbate oral pain," said Sharon Elad, DMD, MSc, of the University of Rochester Medical Center in New York, and Noam Yarom, DMD, of Tel Aviv University in Israel, in an . "Furthermore, the use of a single term for multiple compounds hampers clear communication between professionals, and, ideally, the term should be uniform and describe the actual active ingredients."

For this reason, said Gupta, the American Academy of Nursing use of mixed-medication mouthwash for managing oral mucositis.

Gupta also noted that has shown similar efficacy between a magic mouthwash similar to that used in this Alliance study, chlorhexidine, and a salt and soda mix.

"Given the ease of preparation at home and almost no cost (1 teaspoon of salt and sodium bicarbonate each in 1 liter of water), salt and soda mouthwash is often prescribed by physicians," he said, adding that had this been used in place of the placebo, or as a fourth study arm, it might have demonstrated equivalence or superiority over the investigational agents.

Drowsiness, stinging or burning, and unpleasant taste were examined as secondary outcomes on scales ranging from best to worst (0-10). With the doxepin rinse compared with placebo: drowsiness (1.5 points higher, P=0.03) and unpleasant taste (1.5 points higher, P=0.002) were worse than placebo. No significant differences were seen between the diphenhydramine-lidocaine-antacid and placebo groups.

Grade 3 adverse events occurred in three patients in each of the investigational arms (4%) versus two patients in the placebo group (2%), and five patients receiving the doxepin mouthwash reported fatigue (6%) versus none in the other two arms.

"The distinction between statistical significance and clinical importance is relevant in this study, and the findings suggest that pain relief was short-term and limited among many of the patients," wrote Elad and Yarom. "Nevertheless, this limited effect may be beneficial if doxepin is used as a supplemental analgesic (e.g., to reduce the dose of systemic opioids)."

In a post hoc exploratory responder analysis where 68.4% of placebo patients reported clinically important pain improvement, the magic mouthwash appeared to offer an advantage:

• Doxepin: 79.5%, P=0.14
• Diphenhydramine-lidocaine-antacid: 85.5%, P=0.02

"This suggests that a subgroup of patients may have experienced meaningful benefits from the diphenhydramine-lidocaine-antacid mouthwash," the editorialists wrote.

For the Alliance A221304 study, Miller's team randomized 275 patients (1:1:1) at 30 institutions in the U.S. from 2014 to 2016. All patients had a minimum pain score of 4 (out of 10). In all, 92 patients received the 25-mg doxepin mouthwash (in a 5-mL solution), 92 received a 5-mL placebo mouthwash consisting of water and Ora-Sweet SF (2.5 mL each), and 91 received a 5-mL solution of 12.5 mg diphenhydramine, 2% lidocaine, and an antacid (200 mg of aluminum hydroxide, 200 mg of magnesium hydroxide, and 20 mg of simethicone).

Limitations of the study included the fact that it was only designed to assess pain at up to 4 hours after administration of the mouthwash, while post-radiotherapy pain can persist for days.